Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy

错义突变 扩张型心肌病 遗传学 医学 移码突变 基因型 遗传变异 等位基因 基因 胡说 表型 内科学 生物 心力衰竭
作者
Martin G. Dalin,Pär G. Engström,Emil G. Ivarsson,Per Unneberg,Sara Light,Maria Schaufelberger,Thomas Gilljam,Bert Andersson,Martin O. Bergö
出处
期刊:International Journal of Cardiology [Elsevier]
卷期号:228: 742-748 被引量:19
标识
DOI:10.1016/j.ijcard.2016.11.066
摘要

Germline genetic variants are an important cause of dilated cardiomyopathy (DCM). However, recent sequencing studies have revealed rare variants in DCM-associated genes also in individuals without known heart disease. In this study, we investigate variant prevalence and genotype-phenotype correlations in Swedish DCM patients, and compare their genetic variants to those detected in reference cohorts.We sequenced the coding regions of 41 DCM-associated genes in 176 unrelated patients with idiopathic DCM and found 102 protein-altering variants with an allele frequency of <0.04% in reference cohorts; the majority were missense variants not previously described in DCM. Fifty-five (31%) patients had one variant, and 24 (14%) patients had two or more variants in the analysed genes. Detection of genetic variants in any gene, and in LMNA, MYH7 or TTN alone, was associated with early onset disease and reduced transplant-free survival. As expected, nonsense and frameshift variants were more common in DCM patients than in healthy individuals of the reference cohort 1000 Genomes Europeans. Surprisingly however, the prevalence, conservation and pathogenicity scores, and localization of missense variants were similar in DCM patients and healthy reference individuals.To our knowledge, this is the first study to identify correlations between genotype and prognosis when sequencing a large number of genes in unselected DCM patients. The similar distribution of missense variants in DCM patients and healthy reference individuals questions the pathogenic role of many variants, and suggests that results from genetic testing of DCM patients should be interpreted with caution.
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